It is often important to control the release of an active medicament to achieve a slow release of the medicament over a prolonged period of time extending the duration of the action of the medicament over that achieved by conventional delivery. Many active medicaments in traditional pharmaceutical forms require frequent ingestion of multiple unit doses per day resulting in wide variations in serum concentration throughout the course of treatment and poor patient compliance.
Dempski, et al, U.S. Pat. No. 4,173,626, disclose capsules comprising uncoated indomethacin pellets for immediaterelease, coated indomethacin pellets for prolonged release, and non-medicated pellets as volume fill.
The incorporation of water-insoluble medicament contained in spheroids comprised of microcrystalline cellulose and at least one cellulose derivative into capsules, sachets and cachets is disclosed in U.K. Patent Publication No. GB 2202143.
Concurrently filed, copending U.S. patent application, discloses hard shell capsules filled with carbonic anhydrase inhibitor containing active spherical granules.
Capsules, however, have many drawbacks such as the inability of certain people to swallow capsules, the inability to be divided, and instability. Additionally, capsules are subject to tampering, are relatively hard to manufacture and are relatively expensive to manufacture.
Shepard, U.S. Pat. No. 3,080,294, discloses a sustained release pharmaceutical-tablet comprising an inner core coated with multiple layers of an active medicament mixture, each layer releasing a portion of active medicament as it is successively dissolved. Variations in such coatings result in a lack of uniformity among tablets, and crushing or dividing of the tablet exposes many layers of active medicament resulting in simultaneous release of the active medicament of each layer. The coatings do not encapsulate the medicament.
Amann, U.S. Pat. No. 3,865,935, discloses erythromycin tablets which are stable outside the stomach but which produce immediate action upon disintegration in the stomach. These tablets require sodium citrate or sodium citrate dihydrate and do not yield a controlled release of prolonged duration.
In U.S. Pat. No. 3,115,441, Hermelin discloses irregularly shaped coated analgesic particles in a compressed matrix of the same analgesic.
U.K. Patent Specification No. GB 1,598,458 discloses tablets of brittle microcapsules and other particles with brittle coatings, particularly potassium chloride, with 2 to 20 percent by weight of brittle microcapsules or brittle particles of a water-soluble, natural or synthetic wax which forms a matrix in which the particles are suspended. The tablets must, in a major portion, comprise the active medicament and are particularly deficient in lower dosages.
U.K. Patent Publication No. GB 2,041,222 discloses the tabletting of microcapsules of indoprofen. Other active medicaments may be included in the tablet. The compression of a single type of microcapsules results in crushing of the microcapsule and consequently, the loss of controlled release properties. These tablets are only suitable for high dosage delivery as well because the entire tablet is formed of microcapsules containing active medicament. Additionally, the microcapsules are not formed by spheronization.
Hess, et al, U.S. Pat. No. 4,353,887, discloses a divisible tablet comprising active granules wherein the surface area of the tablet is not materially increased by division.
In Bechgaard, et al, U.S. Pat. No. 4,606,909, the placement of a sparingly soluble active substance such as tetracycline in an oral controlled release dosage form is disclosed.
In Ventouras, U.S. Pat. No. 4,784,858, a controlled release tablet comprising (1) coated cores, not necessarily spheronized, comprising a core of a water-soluble pharmaceutically active substance dispersed in a water-insoluble polymeric excipient and a swellable water-insoluble polymeric substance; and (2) a coating of an elastic, water insoluble and semipermeable diffusion film of a polymer. Here, the core is made to expand with water causing the surface of the coating to extend, making it permeable, and thereby releasing the medicament in the core.
Valorose et al, U.S. Pat. No. 4,837,030, disclose tablets for the controlled release of tetracycline compounds comprising active spherical granules.
Concurrently filed copending application, Ser. No. 031,065, discloses two pulse pharmaceutical delivery systems for 7-dimethylamino-6-deoxy-6-demethyltetracycline or non-toxic acid addition salts thereof comprising initial loading components and pH sensitive polymer coated secondary loading components adapted to provide therapeutically effect blood concentrations of minocycline for up to about 24 hours in a once-a-day dosage.
FIG. 1 is a micrograph of K-Dur.RTM. potassium chloride tablets from Key Pharmaceuticals. The potassium chloride granules (1) are distributed throughout a tablet matrix (3) comprising powdered and/or granular material.
FIG. 2 is a micrograph of PCE.RTM. erythromycin tablets from Abbott Laboratories. The erythromycin granules (5) are distributed throughout a tablet matrix (7) comprising powdered and/or granular material.
FIG. 3 is a micrograph of Theo-Dur.RTM. theophylline anhydrous tablets from Key Pharmaceuticals. The theophylline anhydrous granules (9) are distributed throughout a tablet matrix (11) comprising powdered and/or granular material.
All of these tablets have the disadvantages discussed above including crushing of the active particles with resultant loss of controlled release properties. Furthermore, commercial production of tablets at low dosages according to the prior art is impractical and results in great variability in actual dosages and relatively large tablets.
It has now been discovered that the controlled release properties of active spherical granules can be protected and low dosage oral dosage unit forms can be prepared if the active spherical granules are tabletted with a number of compressible spherical granules which deform or crack at compressible yields lower than the active spherical granules, and therefore before the active spherical granules, sufficiently to cushion the active spherical granules and fill at least a portion of the voids normally created during tabletting. These tablets can be formed into various configurations making them suitable for virtually all orally administered active medicaments and treatments in which controlled release is desirable. Additionally, they are stable, retaining their potency and controlled release properties under a wide range of storage conditions.